[!INFO] Definition of DKA
[!INFO]
For DKA, expected target is resolution of ketonaemia and acidosis in 24 hours.
Replace total fluid deficit in 24 hours
- Second liter of fluid usually requires potassium addion. See [[#Electrolytes]] below.
When to titrate dose:
When to stop:
Until ketones < 0.6 mmol/L OR venous pH > 7.3 OR venous bicarb > 18 mmol/L.
EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave and 'mild' ST depression.
The U-wave is a deflection following the T wave. . Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.
[!INFO] U wave
- mechanism of generation isn't clearly identified
- normal u wave is concordant with the t wave
- it is smaller than the t wave (1/3 size)
- it's size increases with decreasing hear rate
#2022BSQ Q5
[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.
ONLY TAENIA SAGINATA causes CYSTICERCOSIS.
Probably the most common parasitic infection of the CNS.
Pigs are the usual intermediate host, Humans are the definitive host.
cysticercosis results from humans acting as accidental intermediate hosts for the parasite
[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.
Now found that most infections are asymptomatic. However, people infected with cysticercosis usually present due to the neurological symptoms.
Seizures are very common.
Diagnosis: Combintion of imaging and serology are required because there are situations in which only one of the two modalities will show positive results.
Imaging : MRI or CT, Serology: Immunoblot / enzyme linked assasy
Treatment:
Treatment of neurological symptoms with anticonvulsants, reducing cerebral oedema, intracranial pressure etc is the main concern.
Then, cysts are treated if required.
Calcified cysts are dead; antihelminthic therapy won't benefit the patient.
Live cysts: Antihelminthing treatment must be combimed with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite.
Histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease
monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage
| Disease | Pattern |
|---|---|
| Tuberculosis | Caseating (i.e absolutely no cellular structure) granuloma with occasional Langhans giant cells |
| Leprosy | Non caseating granuloma |
| Sarcoidosis | Non caseating, abundant activated macrophages |
| Cat Scratch disease | Rounded or stellate, central debris present. |
| Syphillitic gumma | Central necrosis but with preserved cell outlines, plasma cell infiltrate |
| GPA (granulomatosis with polyangitis) | presence of multinucleated giant cells, interstitial collagen alteration, and the presence of a polymorphous inflammatory infiltrate |
[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
There membranes beging to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.
#2022BSQ Q2
Routes of malignant spread
Primary brain tumours are either
#2022BSQ-MAY Q27
Source:Medscape
Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce [[Hormone Physiology#Calcitonin|Calcitonin]]).
[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold**.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.
Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.
Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.
Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.
Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
No special nuclear features.
Differentiated from benign adenomas by
They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically
Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.
Distant mets for both types occur to lung and bone.
Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.
[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in
- Hashimoto thyroiditis
- multinodular hypoplasia
- lymphocytic thyroidis
- Source
2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.
Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.
Familial cases are multifocal and bilateral.
Sporadic cases are unifolcal.
Histology:
unencapsulated.
Focal calcifications are present.
Characteristic depostion of amyloid is seen in the tumour. <- A unique features in thyroid malignancy.
C cell hyperplasia is unique to familial cases.
Treatment:
Lymph node metastasis is common.
Total thyroidectomy with lymph node clearance is done.
Prophylactic thyroidectomy is done in children diganosed with MEN2 syndromes.
FMTC syndromes:
In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.
[!TIP] Mnemonic for MEN syndromes
පා පා පි
පා මේ ෆි
මා මේ ෆි
[!WARNING] A very, very bad cancer!
It is rare but has the worst prognosis of all thyroid CAs.
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.
Anaplastic CA grows rapidly. Many patients present with local invasion (unresectable tumours) or cervial lymph node metastasis.
On histology, the tumour retains feature so epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.
In adults, bone mets are far more common than primary bone tumours.
Bone is the 3rd commonest site of metastatis next to Lung and liver.
Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).
Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma
Bone mets are commonest in spine, pelvis and thigh.
Osteolytic :
Osteoblastic:
Ignore breast in this list!
Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source
Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.
Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.
Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present
Renal cancer also commonly spreads to bone.
#2022BSQ Q8
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.
Atherosclerosis requires two factors
Anything that exacerbates these two factors will promote atherogenesis.
In the presence of lipids within the intima, macrophages become activated. When they engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.
Plaques can
Factors which make a plaque unstable:
#2022BSQ Q24
Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent
Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.
#2022BSQ Q24
See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasolidation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon
Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)
GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.
Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source
Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source
Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.
[!TIP] All of these hormones generally cause changes which promote digestion and absorption except for somatostatin
CT
[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.
[!INFO] Functions of complement
- Promote inflammation through C3a, C4a and C5a
- Recruit cells (through chemoatractants)
- Kill targeted cells (bacteria)
- Solubility antigen-antibody complexes and remove them from circulation
The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result the more active alternative pathway C3 convertase C3bBb is formed, which is further stabilized by properdin.Source
#2022BSQ Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eleminated by the Reticuloendothelial system. Serum level isn't elevated in kidney disease.
3 isoforms
Skeletal muscle - 99% CK MM
CK-MB = Usually in cardiac muscle. Can also be elevated in elite athletes and normal people after strenuous exercise (i.e can produce false +ve for MI)
CK is usually elevated in myopathies. => there are different types of myopathies
Can also be elevated in a few non myopathic conditions
We went to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.
Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!
Sample is cooled until it is send to the lab to prevent bacterial multiplication affecting the colony count.
8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.
White blood cell casts - renal infection = could be pyelonephritis.
Causes of sterile pyuria:
Source: CVS physiology website.
| pacemaker cells | non pacemaker cells |
|---|---|
| No true resting potential | |
| Continuous action potentials generated | |
| Depolarization due to SLOW calcium current | FAST Na mediated depolarization |
Hyperkalemia
EKG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest. These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.
Hypokalemia
EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave.
The U-wave is a deflection following the T wave. Hypokalemia causes enlarged and prominent T waves on the EKG. Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.
Hypercalcaemia
The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.
Hypocalcemia
The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563
doi.org/10.1016/0002-9149(63)90255-8
Hypermagnesaemia
#2021BSQ-JUL Q31
[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:
- Prostate-Specific Antigen (PSA) - Prostate cancer
- Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
- Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
- CA-125 - Ovarian cancer
- CA 19-9 - Pancreatic cancer, colorectal cancer
- CA 15-3 - Breast cancer
- CA 27-29 - Breast cancer
- Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
- Calcitonin - Medullary thyroid cancer
- Thyroglobulin - Thyroid cancer (papillary and follicular)
- Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
- Chromogranin A - Neuroendocrine tumors
- S-100 Protein - Melanoma, neuroendocrine tumors
- Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
- Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
- 5 HIA - carcinoid tumour
- Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.
BRCA1 and BRCA2 - breast and ovarian cancer.
[!TIP] A great summary!
Source
[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's
| Feature | Crohn's Disease | Ulcerative Colitis |
|---|---|---|
| presentation | Abdominal pain + perianal disease. (although colonic disease can cause PR bleeding) | GI bleeding |
| Endoscopy | Cobblestones + linear ulcers | Diffuse continuous involvement, pseudopolyps |
| Radiography | Fistulae | No fistulae |
| Distribution | (potentially mouth to anus) Terminal ileal involvement Or ileocolitis, skip lesions(+) | No ileal involvement (backwash ileitis possible) |
| Rectal involvement | Possible, may spare the rectum | Rectum always involved |
| Pathology | Transmural involvement(+) (wall to serosa), Granulomas (+) | mucosal and submucosal inflammation |
| Serositis(+), Creeping fat | Crypt abscesses – Crypt abscesses are more common in UC than CD | |
| Management | Resection not curative | Colectomy eliminates illness |
| Epid | Develops in teen and twenties | |
| Complications | Intestinal obstruction / perforation | |
| Extraintestinal manifestations | Toxic megacolon! | |
| Malabsorption (because UC involes only the colon) | ||
| Smoking effect | Increased by smoking | Reduced by smoking! |
Peak incidence for both is between 15-30 years. Buy disease can occur at any age.
[!INFO] 'Positive features' of Ulcerative colitis not seen in Crohn's disease
- Toxic megacolon can occur.
- Marked pseudopolyps
- ? More malignant potential
- Rectal involvement is always present
- primary sclerosing cholangitis (seen mostly with UC)
Ileal resection can cause bile acid malabsorption -> diarrhoea.****
[!TIP] PBC - the C can stand for Cirrhocis or Cholangitis.
[!TIP] When to suspect
Suspect in a middle aged woman with pruritus who has elevated ALP and possible other autoimmune conditions.
[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhocis' in the name -> live tissue is inolved -> interlobular bile ducts are involved.
MCQ Discussion:
Most often diagnosed through routine screening. Usually asymptomatic.
But Fatigue is a prominent presenting symptom. Icterus and pruritus are late signs.
95% of PBC occurs in women aged 40 - 50 years.
There is destruction of small interlobular bile ducts.
Antimitochondrial antibodies are found in all patients. M2 is specific for PBC.
The presence of serum antimitochondrial antibodies (AMA) is a highly specific indication of primary biliary cirrhosis (PBC).
Presentation: Asymptomatic with #hepatomegaly and raised ALP. (raised ALP is often the only abnormal investigation)
Pruritus and fatigue.
Raised cholesterol and Xanthelasma
Associated with many autoimmune conditions.
Histology: portal tract infiltrate with hepatic granulomas; changes start in zone 1.
#2022BSQ BSQ Q49
Types of immunoglobulins and antibodies
IgG IgA IgD IgM IgE
Source
#2022BSQ Q40
Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.
Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.
(U-100) denotes the usual concentration (100 U/ml).
Duration: Short acting.
Controls post prandial glucose rise.
Same AA sequence as human insulin.
Bound to Zinc.
Hexamers must be converted to dimers and monomer before absorption -> leads to a delay in peak concentrations-> should be given 30 minuted before meals.
Duration of action tends to exceede duration of post prandial glucose rise -> risk of hypoglycaemia.
Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.
mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.
Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.
made by recombinant DNA technology.
Subsitution of amino acids produces rapid acting and long acting analogs.
Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset
modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action
Insulin aspart- substitution of aspartic acid for proline at position B28.
Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.
Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.
Rapid acting insulins are move convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.
Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
Can't mix with rapid acting insulins.
Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.
After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.
Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered
Glargine has less nocturnal hypoglycemia than NPH insulin
Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, it has a small peak in it's concentration profile.
Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.
form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.
Site of injection - Limbs are faster than abdomen. (muscle-> increased blood flow)
NPH insulin - leg or buttock preferred for moderate rate of absorption.
Pre meal regular insulin - abdominal wall preferred for rapid absorption.
The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site
#2022BSQ Q48
#2022BSQ-MAY Q46
Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source
[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]
| Type 1 | Type 2 | Type 3 | Type 4 |
|---|---|---|---|
| commonest type | Goodpasture syndrome, autoimmune anaemias, erythroblastosis faetalis | [[2023-SEMPaper#Systemic Lupus Erythematosus SLE|SLE]], serum sickness, reactive arthritis, PSGN, [[2022 November SBR#Rheumatoid arthiritis|Rheumatoid Arthtiris]] | second most common |
| Immediate hypersensitivity - eg analphylaxis | 2-24 hours | days to weeks | 2 days |
| IgE (from plasma cells) mediated | IgG and IgM - bind to own cell surface molecules -> complement activated | IgG and IgM antigen antibody complexes | Cell mediated - non antibody dependant - T cells, monocytes and macrophages |
| degranulation of mast cells and basophils | complement mediated red cell agglutination and other cell lysis | Cytokines which cause cell death and inflammation are released | |
| Type | Alternate name | Examples | Mediators |
|---|---|---|---|
| I | Allergy (immediate) | • Atopy – Anaphylaxis – Asthma – Allergic rhinitis – Angioedema – Food allergy | IgE |
| II | Cytotoxic, antibody-dependent | • Erythroblastosis fetalis • Goodpasture syndrome • Autoimmune anemias, thrombocytopenias | IgG, IgM |
| III | Immune complex disease | • Systemic lupus erythematosus • Serum sickness • Reactive arthritis • Arthrus reaction | Aggregation of antigens IgG, IgM Complement proteins |
| IV | Delayed-type hypersensitivity, cell-mediated, antibody-independent | • Contact dermatitis • Tuberculosis • Chronic transplant rejection | T cells, monocytes, macrophages |
Is when the produced antibodies have the property of stimulating receptors on cells. Best example is Grave's disease.
Source
[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories
Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]
#2022BSQ Q54
[!INFO] A Great table!
[[diarrhoeaInResourceRichSettings.png]] <- A great table!
[!TIP] Watery diarrhoea
"Noninflammatory diarrhea is caused by the action of enterotoxins on the secretory mechanisms of the mucosa of the small intestine, without invasion" - Medscape.Same day:
- Norovirus
- clostridium perfringens
- possibly listeria (pregnancy, immunosuppression, extremes of age)
Next day:
- E coli - enteroroxigenic
- most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults
Same week
- Cyclospora
Weeks later
- Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
- Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools.
^5eaea3
[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"
Let's break it down:
- "Can't" - Campylobacter
- "Assume" - Amoebiasis
- "Everyone's" - E. coli
- "Your" - Yersinia
- "Very" - Vibrio parahaemolyticus
- "Special" - Salmonella
- "Sidekick" - Shigella
Most of these have P-incu of 1-3 days. But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.
Main two pathogens of epidemic diarrhoea
Commonest causes of non epidemic watery diarrhoea - E. coli.
[!TIP] mnemonic
Acute bloody diarrhoea
$$
\Large{C^1S^2E^3}
$$
Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)
#2021BSQ-NOV Q37
Symptoms suggesting diarhoeal illness caused by preformed toxins:
Pin worm.
Humans are considered the only host for E. vermicularis
Infection is commonest in children and institutionalised people.
Treatment is easy; reinfection is also easy.
Commonest symptom: itching in the perianal area, possible with excoriation and seconday bacterial infection.
Perianal itching / scratching contributes to faeco-oral transmission of the parasite.
Infection of the female genital tract can occur. Can cause abdominal pain mimicking appendicitis.
Treatment: Albendazole, mebendazole
Strongyloides stercoralis : thread worm
First discovered in french troops returning from vietnam in the 19th century who developed chronic diarrhoea.
Infective stage : Filariform larva: -> penetrates intact skin.
[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.
Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.
It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)
Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+)
Ivermectin has been shown to be superior to albendazole.
Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.
Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.
#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.
#2022GM Q14
#2021GM-JUL/Q17
Pathogenesis: Autoimmune disease affecting exocrine glands.
In most cases, Sjogren syndrome is only 'irritating' and not dangerous.
Can occur as a primary disorder or secondary to another rheumatic disease.
Symptoms are classified mainly as
Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.
Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.
90% are positive for Rheumatoid factors: Kumar and Clark
Epidemiology: Most Commonly occurs in women aged 50-60 years old.
Keratoconjuntivis sicca - term for the occular manifestations of Sojgrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement; Sojgren's disease is one possible cause of this.
Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.
Objective test: Focal lymphocytic sialadenitis score >= 1;
Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.
Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.
Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.
Vascular:
Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.
inhibition of synthesis of NO in rats restores normal arterial pressure.
? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.
mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)
Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.
Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.
A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.
See hypothesis-highlights on UpToDate
#2022GM Q32
Serum 'to' Ascites Albumin gradient
SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)
Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.
#2022GM Q21
Respiratory epithelium - ciliated pseudostratified columnar epithelium.
Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.
Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.
Commoner in women.
Increases with age; marked increase after 60 years.
Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions
Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$
See [[Lung function tests#Obstructive vs. restrictive diseases]]
Usually affects bilateral lower lobes.
Permanent dilation -> small airways are traceable almost upto the pleura. (in normal lungs, they stop about 2 cm short of the pleura)
Chronic inflammatory exudate is seen.
Extensive desquamation of epithelium causing ulceration.
Healing is usually by fibrosis.
Abscesses can form as complications.
Clinical and CT:
CT features that are reliable signs of bronchiectasis:
Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.
Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response
Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis
Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection
#2022BSQ-MAY Q49
| Defect | Presentation |
|---|---|
| Antibody deficiency | Recurrent sinopulmonary infection / meningitis / chronic GI infections (esp. capsulated organisms - H. Influenza, N. meningitidis, S. pneumonae) |
| Granulocyte (neutrophil) defects | Recurrent soft tissue infection |
| Cell mediated immunity (esp. T cells) | Infection with Viruses, intracellular pathogens, fungi (CMV, EBV, mycobacteria, candida, [[HIV-AIDS|cryptococcus]],[[HIV-AIDS#Pneumocystic jirovecii pneumonia|pneumocystis]] ) |
Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction. See -> [[2021 Basic Sciences July#Natural killer cells]]
***
However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
***
~~>
- Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
- Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
- Recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
- Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
- Marked elevation of serum IgE with multisystem infections -> Job syndrome
~~
| Defect | Outcome | Organism |
|---|---|---|
| low gamma globulin | recurrent enterocolitis and ? sinopulmonary infections | Giardia, enteroviruses, CMV, campylobacter |
| Terminal complement | Recurrent neisseria meningitis | |
| Ig or RET | Recurrent encapsulated pathogen infection | |
| Selective IgA deficiency | Usually asymptomatic; can present with recurrent mucosal pyogenic infections | |
Usually due to defects in B lymphocytes -> not enough antibodies produced.
Recurrent sinopulmonary infections and persistence of gut pathogens.
Leads to bronchiectasis and chronic diarrhoea with malabsorption.
[!INFO] Commonest significant antibody deficiency affecting children and adults.
Diagnosed at: 20 and 45 years of age.
? etiology - few are inherited. Pattern may by #autosomalDominant with low penetrance or #autosomal-Recessive - UpToDate
There is
Lymphoma is a common cause of death in these patients.
Complications:
Chronic giadia infections with malabsorption can occur.
Treatment is IVIG.
Commonest primary immune deficiency.
Individuals are usually asymptomatic. -> treatment is only antibiotics as needed.
Can present with recurrent mucosal pyogenic infections.
#2021BSQ-JUL Q24
Also called hypogammaglobulinaemia.
Mutation of the BTK gene impairs B cell maturation -> causes low or absent mature B cells -> severe hypogammaglobulinaemia.
Commonest inheritance: #x-linked-recessive with mothers being carriers. #autosomal-Recessive inheritance is seen in ? 50%. - confirm
Manifestation: recurrent sinopulmonary infections.(From 6 to 12 months of age, otitis media, sinusitis, bronchitis, and pneumonia).
Common pathogens: Encapsulated pyogenic bacteria Haemophillus influenzae and strep pneumoniae.
Treatment: repeated IVIG transfusions or stem cell transplant.
[[2022-November#Complement system overview]]
Impaired alternative pathways -> non specific impairement -> bacterial infections.
Impaired classical pathway -> increased infection and increased immune complex deposition -> SLE, vasculitis, glomerulonephritis etc.
MAC -> neisseria infections.
#2022BSQ-MAY Q49
Commonest form is impaired #x-linked-recessive .
Defect is in IL-2 receptor.
T and NK cells are lacking in the blood.
Presentation is similar to pure T lymphocyte deficiency:
That is, infections with fungi, protozoa, intracellular organisms.
- persistent and recurrent diarrhoea, otitis media, thrush, and respiratory infections
[[ImmuneResponsesTofungalpathogens.pdf]]
Not as well understood as bacteria and viruses.
Pattern recognition receptors (PRR) on antigen presenting cells are triggered by fungal cell components.
This causes intracellular signalling of the APC which promotes phagocytosis and stimulates killing mechanisms.
The adaptive immunity to fungi is mediated by CD4+ Th1 cells with produce interferron gamma and CD4+ Th17 cells which produce IL-17. They drive killing by innate effector cells like marcophages and neutrophils.
So overall,
Splenectomy leaves the patient vulnerable to infection by capsulated organisms.
More than half of those with OPSI die.
Encapsulated organisms are resistant to phagocytosis without opsonization.
The spleen is a major site of early IgM production.
IgM memory B cells produce IgM to promote the clearance of polysaccharide-encapsulated bacteria.
Although the total B lymphocytes remain intact, a significant fall in the levels of memory B cells and switched B cell proportions are usually encountered 150 days post-splenectomy. This acts as a particular predisposition to infections caused by polysaccharide-encapsulated bacteria and is responsible for a diminished immunological response to polysaccharide vaccines
Source
However, even after opsonization, the bacteria must be phagocytosed. Splenic macrophages are a major contributor to this phagocytosis.
So in asplenia, there is impaired IgM production and thus opsonization and also impaired phagocytosis.
"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".
There are 18 different types of systemic and 22 localized forms of amyloidosis
The four most common causes of systemic amyloid deposition are
[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.
| Type | Constituent |
|---|---|
| AL Amyloidosis | Deposition of Ig Light chain fragments |
| Transthyretin amyloidosis | |
| AA amyloidosis | serum amyloid protein - acute phase reactant; Most common form in resource limited countries - occurs due to chronic inflammation |
Other forms of amyloidosis:
Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.
When congo red stains binds to amyloid protein, it produces apple green birefringence.
Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)
AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)
There is multisystem amyloid deposition
Fatigue, non intentional weight loss
Heavy proteinuria (70%) - nephrotic syndrome
oedema
#hepatosplenomegaly (hepatomegaly +/- splenomegaly seen in 70%)
Cardiomyopathy and heart failure (60%) - thickening of interventricular septum is present / MI due to accumulation of amyloid in coronaries.
Neuropathies - carpal tunnel, mixed sensory and motor peripheral neuropathy is a prominent feature in AL amyloidosis. (Symptoms of numbness, paresthesia, and pain are frequent)
Amyloid infiltration of muscles - macroglossia with scalloping and shoulder pad sign. (also enlarged deltoids)
Skin - purpura (raccoon eyes with valsalva maneuver is specific), waxy skin, easy bruising.
Coagulopathy - possibly due to factor X binding of coagulation factors to amyloid.
GI involvement: gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from *dysmotility
Bortezomi based induction
Melphalan
Haematopoietic cell transplantation.
This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.
The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.
AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.
SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis
In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.
Spondylos = greek for vertebrae
Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis
Sacroiliac joint:
sclerosis,
joint space widening, or erosion (fusion in late stages)
syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.
A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.
Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.
#TODO add image of enthesis
#2022GM Q25
#2022GM Q27
Ankylosing = stiffness or fixation of a joint by disease
Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)
Some terminology: not super important
SourceGreat article!
HLA-B27
[!INFO] Key points
- It's largely a genetic disease - Patient's children have increased risk of getting it
- Pathogenesis consists of inflammation, bone erosion and syndesmophyte formation.
- Bone erosion and syndesmophyte formation are probably not linked to inflammation
- TNF-blockage suppresses symptoms but doesn't arrest bone changes.
#2022GM Q30
Congenital
Acquired
Hepatosplenomegaly and lymphadenopathy are rare.
#2022BSQ Q5
[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.
ONLY TAENIA SAGINATA causes CYSTICERCOSIS.
Probably the most common parasitic infection of the CNS.
Pigs are the usual intermediate host, Humans are the definitive host.
cysticercosis results from humans acting as accidental intermediate hosts for the parasite
[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.
Now found that most infections are asymptomatic. However, people infected with cysticercosis usually present due to the neurological symptoms.
Seizures are very common.
Diagnosis: Combintion of imaging and serology are required because there are situations in which only one of the two modalities will show positive results.
Imaging : MRI or CT, Serology: Immunoblot / enzyme linked assasy
Treatment:
Treatment of neurological symptoms with anticonvulsants, reducing cerebral oedema, intracranial pressure etc is the main concern.
Then, cysts are treated if required.
Calcified cysts are dead; antihelminthic therapy won't benefit the patient.
Live cysts: Antihelminthing treatment must be combimed with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite.
Histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease
monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage
| Disease | Pattern |
|---|---|
| Tuberculosis | Caseating (i.e absolutely no cellular structure) granuloma with occasional Langhans giant cells |
| Leprosy | Non caseating granuloma |
| Sarcoidosis | Non caseating, abundant activated macrophages |
| Cat Scratch disease | Rounded or stellate, central debris present. |
| Syphillitic gumma | Central necrosis but with preserved cell outlines, plasma cell infiltrate |
| GPA (granulomatosis with polyangitis) | presence of multinucleated giant cells, interstitial collagen alteration, and the presence of a polymorphous inflammatory infiltrate |
[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
There membranes beging to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.
#2022BSQ Q2
Routes of malignant spread
Primary brain tumours are either
#2022BSQ-MAY Q27
Source:Medscape
Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce [[Hormone Physiology#Calcitonin|Calcitonin]]).
[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold**.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.
Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.
Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.
Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.
Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
No special nuclear features.
Differentiated from benign adenomas by
They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically
Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.
Distant mets for both types occur to lung and bone.
Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.
[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in
- Hashimoto thyroiditis
- multinodular hypoplasia
- lymphocytic thyroidis
- Source
2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.
Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.
Familial cases are multifocal and bilateral.
Sporadic cases are unifolcal.
Histology:
unencapsulated.
Focal calcifications are present.
Characteristic depostion of amyloid is seen in the tumour. <- A unique features in thyroid malignancy.
C cell hyperplasia is unique to familial cases.
Treatment:
Lymph node metastasis is common.
Total thyroidectomy with lymph node clearance is done.
Prophylactic thyroidectomy is done in children diganosed with MEN2 syndromes.
FMTC syndromes:
In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.
[!TIP] Mnemonic for MEN syndromes
පා පා පි
පා මේ ෆි
මා මේ ෆි
[!WARNING] A very, very bad cancer!
It is rare but has the worst prognosis of all thyroid CAs.
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.
Anaplastic CA grows rapidly. Many patients present with local invasion (unresectable tumours) or cervial lymph node metastasis.
On histology, the tumour retains feature so epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.
In adults, bone mets are far more common than primary bone tumours.
Bone is the 3rd commonest site of metastatis next to Lung and liver.
Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).
Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma
Bone mets are commonest in spine, pelvis and thigh.
Osteolytic :
Osteoblastic:
Ignore breast in this list!
Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source
Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.
Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.
Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present
Renal cancer also commonly spreads to bone.
#2022BSQ Q8
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.
Atherosclerosis requires two factors
Anything that exacerbates these two factors will promote atherogenesis.
In the presence of lipids within the intima, macrophages become activated. When they engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.
Plaques can
Factors which make a plaque unstable:
#2022BSQ Q24
Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent
Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.
#2022BSQ Q24
See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasolidation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon
Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)
GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.
Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source
Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source
Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.
[!TIP] All of these hormones generally cause changes which promote digestion and absorption except for somatostatin
CT
[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.
[!INFO] Functions of complement
- Promote inflammation through C3a, C4a and C5a
- Recruit cells (through chemoatractants)
- Kill targeted cells (bacteria)
- Solubility antigen-antibody complexes and remove them from circulation
The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result the more active alternative pathway C3 convertase C3bBb is formed, which is further stabilized by properdin.Source
#2022BSQ Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eleminated by the Reticuloendothelial system. Serum level isn't elevated in kidney disease.
3 isoforms
Skeletal muscle - 99% CK MM
CK-MB = Usually in cardiac muscle. Can also be elevated in elite athletes and normal people after strenuous exercise (i.e can produce false +ve for MI)
CK is usually elevated in myopathies. => there are different types of myopathies
Can also be elevated in a few non myopathic conditions
We went to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.
Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!
Sample is cooled until it is send to the lab to prevent bacterial multiplication affecting the colony count.
8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.
White blood cell casts - renal infection = could be pyelonephritis.
Causes of sterile pyuria:
Source: CVS physiology website.
| pacemaker cells | non pacemaker cells |
|---|---|
| No true resting potential | |
| Continuous action potentials generated | |
| Depolarization due to SLOW calcium current | FAST Na mediated depolarization |
Hyperkalemia
EKG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest. These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.
Hypokalemia
EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave.
The U-wave is a deflection following the T wave. Hypokalemia causes enlarged and prominent T waves on the EKG. Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.
Hypercalcaemia
The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.
Hypocalcemia
The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563
doi.org/10.1016/0002-9149(63)90255-8
Hypermagnesaemia
#2021BSQ-JUL Q31
[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:
- Prostate-Specific Antigen (PSA) - Prostate cancer
- Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
- Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
- CA-125 - Ovarian cancer
- CA 19-9 - Pancreatic cancer, colorectal cancer
- CA 15-3 - Breast cancer
- CA 27-29 - Breast cancer
- Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
- Calcitonin - Medullary thyroid cancer
- Thyroglobulin - Thyroid cancer (papillary and follicular)
- Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
- Chromogranin A - Neuroendocrine tumors
- S-100 Protein - Melanoma, neuroendocrine tumors
- Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
- Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
- 5 HIA - carcinoid tumour
- Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.
BRCA1 and BRCA2 - breast and ovarian cancer.
[!TIP] A great summary!
Source
[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's
| Feature | Crohn's Disease | Ulcerative Colitis |
|---|---|---|
| presentation | Abdominal pain + perianal disease. (although colonic disease can cause PR bleeding) | GI bleeding |
| Endoscopy | Cobblestones + linear ulcers | Diffuse continuous involvement, pseudopolyps |
| Radiography | Fistulae | No fistulae |
| Distribution | (potentially mouth to anus) Terminal ileal involvement Or ileocolitis, skip lesions(+) | No ileal involvement (backwash ileitis possible) |
| Rectal involvement | Possible, may spare the rectum | Rectum always involved |
| Pathology | Transmural involvement(+) (wall to serosa), Granulomas (+) | mucosal and submucosal inflammation |
| Serositis(+), Creeping fat | Crypt abscesses – Crypt abscesses are more common in UC than CD | |
| Management | Resection not curative | Colectomy eliminates illness |
| Epid | Develops in teen and twenties | |
| Complications | Intestinal obstruction / perforation | |
| Extraintestinal manifestations | Toxic megacolon! | |
| Malabsorption (because UC involes only the colon) | ||
| Smoking effect | Increased by smoking | Reduced by smoking! |
Peak incidence for both is between 15-30 years. Buy disease can occur at any age.
[!INFO] 'Positive features' of Ulcerative colitis not seen in Crohn's disease
- Toxic megacolon can occur.
- Marked pseudopolyps
- ? More malignant potential
- Rectal involvement is always present
- primary sclerosing cholangitis (seen mostly with UC)
Ileal resection can cause bile acid malabsorption -> diarrhoea.****
[!TIP] PBC - the C can stand for Cirrhocis or Cholangitis.
[!TIP] When to suspect
Suspect in a middle aged woman with pruritus who has elevated ALP and possible other autoimmune conditions.
[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhocis' in the name -> live tissue is inolved -> interlobular bile ducts are involved.
MCQ Discussion:
Most often diagnosed through routine screening. Usually asymptomatic.
But Fatigue is a prominent presenting symptom. Icterus and pruritus are late signs.
95% of PBC occurs in women aged 40 - 50 years.
There is destruction of small interlobular bile ducts.
Antimitochondrial antibodies are found in all patients. M2 is specific for PBC.
The presence of serum antimitochondrial antibodies (AMA) is a highly specific indication of primary biliary cirrhosis (PBC).
Presentation: Asymptomatic with #hepatomegaly and raised ALP. (raised ALP is often the only abnormal investigation)
Pruritus and fatigue.
Raised cholesterol and Xanthelasma
Associated with many autoimmune conditions.
Histology: portal tract infiltrate with hepatic granulomas; changes start in zone 1.
#2022BSQ BSQ Q49
Types of immunoglobulins and antibodies
IgG IgA IgD IgM IgE
Source
#2022BSQ Q40
Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.
Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.
(U-100) denotes the usual concentration (100 U/ml).
Duration: Short acting.
Controls post prandial glucose rise.
Same AA sequence as human insulin.
Bound to Zinc.
Hexamers must be converted to dimers and monomer before absorption -> leads to a delay in peak concentrations-> should be given 30 minuted before meals.
Duration of action tends to exceede duration of post prandial glucose rise -> risk of hypoglycaemia.
Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.
mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.
Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.
made by recombinant DNA technology.
Subsitution of amino acids produces rapid acting and long acting analogs.
Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset
modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action
Insulin aspart- substitution of aspartic acid for proline at position B28.
Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.
Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.
Rapid acting insulins are move convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.
Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
Can't mix with rapid acting insulins.
Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.
After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.
Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered
Glargine has less nocturnal hypoglycemia than NPH insulin
Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, it has a small peak in it's concentration profile.
Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.
form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.
Site of injection - Limbs are faster than abdomen. (muscle-> increased blood flow)
NPH insulin - leg or buttock preferred for moderate rate of absorption.
Pre meal regular insulin - abdominal wall preferred for rapid absorption.
The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site
#2022BSQ Q48
#2022BSQ-MAY Q46
Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source
[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]
| Type 1 | Type 2 | Type 3 | Type 4 |
|---|---|---|---|
| commonest type | Goodpasture syndrome, autoimmune anaemias, erythroblastosis faetalis | [[2023-SEMPaper#Systemic Lupus Erythematosus SLE|SLE]], serum sickness, reactive arthritis, PSGN, [[2022 November SBR#Rheumatoid arthiritis|Rheumatoid Arthtiris]] | second most common |
| Immediate hypersensitivity - eg analphylaxis | 2-24 hours | days to weeks | 2 days |
| IgE (from plasma cells) mediated | IgG and IgM - bind to own cell surface molecules -> complement activated | IgG and IgM antigen antibody complexes | Cell mediated - non antibody dependant - T cells, monocytes and macrophages |
| degranulation of mast cells and basophils | complement mediated red cell agglutination and other cell lysis | Cytokines which cause cell death and inflammation are released | |
| Type | Alternate name | Examples | Mediators |
|---|---|---|---|
| I | Allergy (immediate) | • Atopy – Anaphylaxis – Asthma – Allergic rhinitis – Angioedema – Food allergy | IgE |
| II | Cytotoxic, antibody-dependent | • Erythroblastosis fetalis • Goodpasture syndrome • Autoimmune anemias, thrombocytopenias | IgG, IgM |
| III | Immune complex disease | • Systemic lupus erythematosus • Serum sickness • Reactive arthritis • Arthrus reaction | Aggregation of antigens IgG, IgM Complement proteins |
| IV | Delayed-type hypersensitivity, cell-mediated, antibody-independent | • Contact dermatitis • Tuberculosis • Chronic transplant rejection | T cells, monocytes, macrophages |
Is when the produced antibodies have the property of stimulating receptors on cells. Best example is Grave's disease.
Source
[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories
Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]
#2022BSQ Q54
[!INFO] A Great table!
[[diarrhoeaInResourceRichSettings.png]] <- A great table!
[!TIP] Watery diarrhoea
"Noninflammatory diarrhea is caused by the action of enterotoxins on the secretory mechanisms of the mucosa of the small intestine, without invasion" - Medscape.Same day:
- Norovirus
- clostridium perfringens
- possibly listeria (pregnancy, immunosuppression, extremes of age)
Next day:
- E coli - enteroroxigenic
- most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults
Same week
- Cyclospora
Weeks later
- Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
- Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools.
^5eaea3
[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"
Let's break it down:
- "Can't" - Campylobacter
- "Assume" - Amoebiasis
- "Everyone's" - E. coli
- "Your" - Yersinia
- "Very" - Vibrio parahaemolyticus
- "Special" - Salmonella
- "Sidekick" - Shigella
Most of these have P-incu of 1-3 days. But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.
Main two pathogens of epidemic diarrhoea
Commonest causes of non epidemic watery diarrhoea - E. coli.
[!TIP] mnemonic
Acute bloody diarrhoea
$$
\Large{C^1S^2E^3}
$$
Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)
#2021BSQ-NOV Q37
Symptoms suggesting diarhoeal illness caused by preformed toxins:
Pin worm.
Humans are considered the only host for E. vermicularis
Infection is commonest in children and institutionalised people.
Treatment is easy; reinfection is also easy.
Commonest symptom: itching in the perianal area, possible with excoriation and seconday bacterial infection.
Perianal itching / scratching contributes to faeco-oral transmission of the parasite.
Infection of the female genital tract can occur. Can cause abdominal pain mimicking appendicitis.
Treatment: Albendazole, mebendazole
Strongyloides stercoralis : thread worm
First discovered in french troops returning from vietnam in the 19th century who developed chronic diarrhoea.
Infective stage : Filariform larva: -> penetrates intact skin.
[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.
Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.
It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)
Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+)
Ivermectin has been shown to be superior to albendazole.
Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.
Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.
#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.
#2022GM Q14
#2021GM-JUL/Q17
Pathogenesis: Autoimmune disease affecting exocrine glands.
In most cases, Sjogren syndrome is only 'irritating' and not dangerous.
Can occur as a primary disorder or secondary to another rheumatic disease.
Symptoms are classified mainly as
Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.
Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.
90% are positive for Rheumatoid factors: Kumar and Clark
Epidemiology: Most Commonly occurs in women aged 50-60 years old.
Keratoconjuntivis sicca - term for the occular manifestations of Sojgrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement; Sojgren's disease is one possible cause of this.
Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.
Objective test: Focal lymphocytic sialadenitis score >= 1;
Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.
Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.
Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.
Vascular:
Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.
inhibition of synthesis of NO in rats restores normal arterial pressure.
? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.
mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)
Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.
Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.
A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.
See hypothesis-highlights on UpToDate
#2022GM Q32
Serum 'to' Ascites Albumin gradient
SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)
Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.
#2022GM Q21
Respiratory epithelium - ciliated pseudostratified columnar epithelium.
Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.
Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.
Commoner in women.
Increases with age; marked increase after 60 years.
Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions
Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$
See [[Lung function tests#Obstructive vs. restrictive diseases]]
Usually affects bilateral lower lobes.
Permanent dilation -> small airways are traceable almost upto the pleura. (in normal lungs, they stop about 2 cm short of the pleura)
Chronic inflammatory exudate is seen.
Extensive desquamation of epithelium causing ulceration.
Healing is usually by fibrosis.
Abscesses can form as complications.
Clinical and CT:
CT features that are reliable signs of bronchiectasis:
Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.
Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response
Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis
Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection
#2022BSQ-MAY Q49
| Defect | Presentation |
|---|---|
| Antibody deficiency | Recurrent sinopulmonary infection / meningitis / chronic GI infections (esp. capsulated organisms - H. Influenza, N. meningitidis, S. pneumonae) |
| Granulocyte (neutrophil) defects | Recurrent soft tissue infection |
| Cell mediated immunity (esp. T cells) | Infection with Viruses, intracellular pathogens, fungi (CMV, EBV, mycobacteria, candida, [[HIV-AIDS|cryptococcus]],[[HIV-AIDS#Pneumocystic jirovecii pneumonia|pneumocystis]] ) |
Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction. See -> [[2021 Basic Sciences July#Natural killer cells]]
***
However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
***
~~>
- Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
- Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
- Recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
- Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
- Marked elevation of serum IgE with multisystem infections -> Job syndrome
~~
| Defect | Outcome | Organism |
|---|---|---|
| low gamma globulin | recurrent enterocolitis and ? sinopulmonary infections | Giardia, enteroviruses, CMV, campylobacter |
| Terminal complement | Recurrent neisseria meningitis | |
| Ig or RET | Recurrent encapsulated pathogen infection | |
| Selective IgA deficiency | Usually asymptomatic; can present with recurrent mucosal pyogenic infections | |
Usually due to defects in B lymphocytes -> not enough antibodies produced.
Recurrent sinopulmonary infections and persistence of gut pathogens.
Leads to bronchiectasis and chronic diarrhoea with malabsorption.
[!INFO] Commonest significant antibody deficiency affecting children and adults.
Diagnosed at: 20 and 45 years of age.
? etiology - few are inherited. Pattern may by #autosomalDominant with low penetrance or #autosomal-Recessive - UpToDate
There is
Lymphoma is a common cause of death in these patients.
Complications:
Chronic giadia infections with malabsorption can occur.
Treatment is IVIG.
Commonest primary immune deficiency.
Individuals are usually asymptomatic. -> treatment is only antibiotics as needed.
Can present with recurrent mucosal pyogenic infections.
#2021BSQ-JUL Q24
Also called hypogammaglobulinaemia.
Mutation of the BTK gene impairs B cell maturation -> causes low or absent mature B cells -> severe hypogammaglobulinaemia.
Commonest inheritance: #x-linked-recessive with mothers being carriers. #autosomal-Recessive inheritance is seen in ? 50%. - confirm
Manifestation: recurrent sinopulmonary infections.(From 6 to 12 months of age, otitis media, sinusitis, bronchitis, and pneumonia).
Common pathogens: Encapsulated pyogenic bacteria Haemophillus influenzae and strep pneumoniae.
Treatment: repeated IVIG transfusions or stem cell transplant.
[[2022-November#Complement system overview]]
Impaired alternative pathways -> non specific impairement -> bacterial infections.
Impaired classical pathway -> increased infection and increased immune complex deposition -> SLE, vasculitis, glomerulonephritis etc.
MAC -> neisseria infections.
#2022BSQ-MAY Q49
Commonest form is impaired #x-linked-recessive .
Defect is in IL-2 receptor.
T and NK cells are lacking in the blood.
Presentation is similar to pure T lymphocyte deficiency:
That is, infections with fungi, protozoa, intracellular organisms.
- persistent and recurrent diarrhoea, otitis media, thrush, and respiratory infections
[[ImmuneResponsesTofungalpathogens.pdf]]
Not as well understood as bacteria and viruses.
Pattern recognition receptors (PRR) on antigen presenting cells are triggered by fungal cell components.
This causes intracellular signalling of the APC which promotes phagocytosis and stimulates killing mechanisms.
The adaptive immunity to fungi is mediated by CD4+ Th1 cells with produce interferron gamma and CD4+ Th17 cells which produce IL-17. They drive killing by innate effector cells like marcophages and neutrophils.
So overall,
Splenectomy leaves the patient vulnerable to infection by capsulated organisms.
More than half of those with OPSI die.
Encapsulated organisms are resistant to phagocytosis without opsonization.
The spleen is a major site of early IgM production.
IgM memory B cells produce IgM to promote the clearance of polysaccharide-encapsulated bacteria.
Although the total B lymphocytes remain intact, a significant fall in the levels of memory B cells and switched B cell proportions are usually encountered 150 days post-splenectomy. This acts as a particular predisposition to infections caused by polysaccharide-encapsulated bacteria and is responsible for a diminished immunological response to polysaccharide vaccines
Source
However, even after opsonization, the bacteria must be phagocytosed. Splenic macrophages are a major contributor to this phagocytosis.
So in asplenia, there is impaired IgM production and thus opsonization and also impaired phagocytosis.
"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".
There are 18 different types of systemic and 22 localized forms of amyloidosis
The four most common causes of systemic amyloid deposition are
[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.
| Type | Constituent |
|---|---|
| AL Amyloidosis | Deposition of Ig Light chain fragments |
| Transthyretin amyloidosis | |
| AA amyloidosis | serum amyloid protein - acute phase reactant; Most common form in resource limited countries - occurs due to chronic inflammation |
Other forms of amyloidosis:
Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.
When congo red stains binds to amyloid protein, it produces apple green birefringence.
Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)
AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)
There is multisystem amyloid deposition
Fatigue, non intentional weight loss
Heavy proteinuria (70%) - nephrotic syndrome
oedema
#hepatosplenomegaly (hepatomegaly +/- splenomegaly seen in 70%)
Cardiomyopathy and heart failure (60%) - thickening of interventricular septum is present / MI due to accumulation of amyloid in coronaries.
Neuropathies - carpal tunnel, mixed sensory and motor peripheral neuropathy is a prominent feature in AL amyloidosis. (Symptoms of numbness, paresthesia, and pain are frequent)
Amyloid infiltration of muscles - macroglossia with scalloping and shoulder pad sign. (also enlarged deltoids)
Skin - purpura (raccoon eyes with valsalva maneuver is specific), waxy skin, easy bruising.
Coagulopathy - possibly due to factor X binding of coagulation factors to amyloid.
GI involvement: gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from *dysmotility
Bortezomi based induction
Melphalan
Haematopoietic cell transplantation.
This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.
The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.
AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.
SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis
In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.
Spondylos = greek for vertebrae
Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis
Sacroiliac joint:
sclerosis,
joint space widening, or erosion (fusion in late stages)
syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.
A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.
Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.
#TODO add image of enthesis
#2022GM Q25
#2022GM Q27
Ankylosing = stiffness or fixation of a joint by disease
Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)
Some terminology: not super important
SourceGreat article!
HLA-B27
[!INFO] Key points
- It's largely a genetic disease - Patient's children have increased risk of getting it
- Pathogenesis consists of inflammation, bone erosion and syndesmophyte formation.
- Bone erosion and syndesmophyte formation are probably not linked to inflammation
- TNF-blockage suppresses symptoms but doesn't arrest bone changes.
#2022GM Q30
Congenital
Acquired
Hepatosplenomegaly and lymphadenopathy are rare.